As discussed in my previous blog, there are many factors that need to be considered when selecting an effective maintenance temperature. Those factors include volume, handling processes, storage, and equipment. In part two of this blog series, I will focus on the impact that some of these variables can have on determining an optimum maintenance temperature for advanced therapies.
The best way to ensure a product is maintained at the right temperature is to ensure that the software, equipment, and processes used are compliant with the products’ requirements throughout the chain of custody. This means that at every step of a product’s journey, all processes and equipment need to be validated.
For example, we recommend completing temperature mapping studies for all movements of a drug after manufacturing is complete. This includes the hand-off and transit to short term or long term storage, receipt and inventory,packaging and labeling, and clinical distribution. Just think about what temperatures an advanced therapy might be exposed to as it moves in and out of a storage tank. Will it make a difference if the therapy starts at -196°C or -135°C when it is exposed to ambient temperature? What about the number of exposures there are as a drug moves through its entire journey?
This is critical information for determining an optimum maintenance temperature and is important in determining whether a lower static storage temperature is necessary.
The same holds true for storage equipment. The vast majority of LN2 storage equipment has a graduated temperature profile; meaning that the product stored at the bottom of the dewar are colder than those stored at the top. The temperature differential from bottom to top varies from manufacturer to manufacturer and product to product. For example, LN2 storage units can be as cold as -196°C at the bottom of the tank and as warm as -135°C at the top.
This means that if, for example, the storage temperature is -150°C, only 65% of the storage dewar can be used. We know this because at Fisher BioServices, all of our storage tanks are thoroughly tested and validated to ensure they perform and operate within the required temperature range (-150°C to -196°C). As an example, some of the testing that is performed includes a 24-hour temperature distribution thermal mapping study, an open lid thermal mapping study, a 24-hour LN2 evaporation rate study, and a 24-hour operating temperature thermal mapping study for a loaded storage system.
The other primary consideration in selecting a maintenance temperature with regard to equipment is temperature recovery time. How often will something be added or retrieved from the storage vessel and how long will it take for the storage unit to recover (i.e., return to the optimal static storage temperature)? The more often a storage vessel is opened, the more potential there is for the product at the top of the unit to be exposed. This determination can be made by performing a series of “open door” studies. In these studies, Fisher BioServices evaluates both the impact on temperature of multiple door openings and the effect based on the length of time the door is open.
Selecting the proper temperature to maintain a viable and potent cell therapy product is a complex operation that must be approached with the same scientific vigor that went into developing the product. Validation studies at every step in the supply chain are an important tool in the development of a cell therapy. They ensure procedures are robust and will reduce variability in processes. The information above is not intended to be a definitive tool in developing a proper temperature profile, but rather a vehicle to begin the discussion. To learn more about maintaining temperature throughout logistical activities, please read our eBook Cold Chain Qualification: 5 Questions You Must Ask When Shipping Biologics!